心肌缺血再灌注损伤中TRAF1的作用及其机制研究

Ischemia heart disease is a major cause of death and disability worldwide, while myocardial ischemia/reperfusion (I/R) injury becomes the biggest problem that threats the life and health of patients after heart surgery. Myocaridal I/R injury is a multifaceted process that is regulated by a complex molecular network. The exploration of the core molecules in its regulatory network is of great significance for the prevention and treatment of myocardial I/R injury. TRAF1, an adapter in multiple signaling pathways, is involved in immunity and in apoptosis in various cell types. However, little is known about its function and the molecular mechanism of its activation during myocardial I/R injury. Our preliminary findings showed that cardiac specific TRAF1 deficiency protect the heart against I/R injury, indicating that TRAF1 is a key mediator of myocardial I/R injury. In this project, we will clarify the role of TRAF1 in myocardial I/R injury in in vivo mouse I/R and in vitro hypoxia/reoxygenation (H/R) cell model. Next, we will search for the downstream target of TRAF1 using interacting proteomic analysis and clarify the mechanism of TRAF1 in regulating myocardial I/R injury, which will provide new avenues for the treatment and prevention of myocardial I/R injury.

缺血性心脏病是威胁着人类的健康和生命的主要疾病，而心肌缺血再灌注损伤则是阻碍和影响各类缺血性心脏病手术疗效的关键难题。心肌缺血再灌注损伤机制复杂，探索其调控网络中的核心分子，对于防治心肌缺血再灌注损伤具有重要的意义。作为多个信号通路中的关键接头蛋白，TRAF1在天然免疫与细胞凋亡中均发挥着重要功能。然而，TRAF1在心肌缺血再灌注损伤中的作用和机制国内外尚无研究报道。我们前期研究结果显示心肌特异性TRAF1基因敲除能显著降低心肌缺血再灌注损伤，提示我们TRAF1是介导心肌缺血再灌注损伤的关键分子。本项目拟应用TRAF1基因工程小鼠和原代心肌细胞，分别建立心肌缺血再灌注的在体和细胞模型，明确TRAF1对心肌缺血再灌注损伤的作用。然后利用互作蛋白组学分析系统搜寻TRAF1的下游靶蛋白，阐明TRAF1调控心肌缺血再灌注损伤的分子机制，以期为防治心肌缺血再灌注损伤提供新的分子靶点。

非酒精性脂肪性肝炎（NASH）正成为肝细胞癌（HCC）的主要病因之一。索拉非尼是治疗晚期肝癌的唯一一线药物，尽管当前临床使用剂量会带来一系列副作用。在这项研究中，我们发现不到当前临床应用的十分之一的低剂量索拉菲尼在小鼠模型上显著改善NASH主要病理特征，包括肝脂肪变性，炎症和纤维化，且没有引起副作用。更令人鼓舞的是，在猴子模型中也观察到了低剂量索拉非尼对NASH治疗的治疗益处。机制上，我们证明索拉菲尼不依赖于其传统激酶抑制剂活性，而是通过诱导线粒体解偶联，降低ATP生成，增加AMP/ATP比率，从而激活AMPK通路。因此，我们的研究揭示了一个从未被发现的索拉菲尼应用于NASH治疗的新方案以及索拉菲尼调控线粒体代谢的新机制。